1-110603567-C-T

Position:

• chr1-110603567-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate

The NM_004974.4(KCNA2):​c.1216G>A​(p.Val406Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V406F) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNA2 NM_004974.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.90

Genes affected

KCNA2 (HGNC:6220): (potassium voltage-gated channel subfamily A member 2) Potassium channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. Four sequence-related potassium channel genes - shaker, shaw, shab, and shal - have been identified in Drosophila, and each has been shown to have human homolog(s). This gene encodes a member of the potassium channel, voltage-gated, shaker-related subfamily. This member contains six membrane-spanning domains with a shaker-type repeat in the fourth segment. It belongs to the delayed rectifier class, members of which allow nerve cells to efficiently repolarize following an action potential. The coding region of this gene is intronless, and the gene is clustered with genes KCNA3 and KCNA10 on chromosome 1. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_004974.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-110603567-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 542666.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KCNA2. . Gene score misZ: 3.831 (greater than the threshold 3.09). Trascript score misZ: 5.1665 (greater than threshold 3.09). The gene has 37 curated pathogenic missense variants (we use a threshold of 10). The gene has 14 curated benign missense variants. GenCC has associacion of the gene with undetermined early-onset epileptic encephalopathy, developmental and epileptic encephalopathy, developmental and epileptic encephalopathy, 32.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.879

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNA2	NM_004974.4	c.1216G>A	p.Val406Ile	missense_variant	3/3	ENST00000316361.10	NP_004965.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNA2	ENST00000316361.10	c.1216G>A	p.Val406Ile	missense_variant	3/3	2	NM_004974.4	ENSP00000314520.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 32 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Clinical Genomics Laboratory, Washington University in St. Louis	Jun 09, 2024	The KCNA2 c.1216G>A (p.Val406Ile) variant, to our knowledge, has not been reported in the medical literature. This variant is absent from the general population (gnomAD v.2.1.1), indicating it is not a common variant. Computational predictors indicate that the variant is damaging, evidence that correlates with impact to KCNA2 function. Another variant in the same codon, c.1216G>T (p.Val406Phe), has been reported in affected individuals and is considered pathogenic and likely pathogenic (ClinVar Variation ID: 542666). A recurrent variant nearby, c.1214C>T (p.Pro405Leu), has been reported as pathogenic as it affects the highly conserved pore domain responsible for gating ion flow (Syrbe S et al., PMID: 25751627). Due to limited information, and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), the clinical significance of this variant is uncertain at this time. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 18, 2020	This sequence change replaces valine with isoleucine at codon 406 of the KCNA2 protein (p.Val406Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with KCNA2-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KCNA2 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	D;.;.;D;D;D;D;.
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	.;D;D;.;.;.;D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.6	L;.;.;L;L;L;L;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.88	.;.;.;.;N;.;N;.
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0010	.;.;.;.;D;.;D;.
Sift4G	Uncertain	0.0020	D;.;.;.;D;.;D;.
Polyphen		0.99	D;.;.;D;D;D;D;.
Vest4		0.70
MutPred		0.79		Loss of catalytic residue at V406 (P = 0.1683);.;.;Loss of catalytic residue at V406 (P = 0.1683);Loss of catalytic residue at V406 (P = 0.1683);Loss of catalytic residue at V406 (P = 0.1683);Loss of catalytic residue at V406 (P = 0.1683);.;
MVP		0.94
MPC		2.1
ClinPred		0.98	D
GERP RS		5.2
Varity_R		0.68
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-111146189;